“Every accomplishment starts with the decision to try. The challenge is not to go where the path may lead, but to go instead where there is no path and leave a trail.” Ralph Waldo Emerson Colophon: Author: Rama Mohamed Kamal Design and lay-out: Mirakels Ontwerp Cover Design: Gildeprint - The Netherlands Printing: Gildeprint - The Netherlands ISBN: ©Rama Mohamed Kamal, 2016 All rights reserved. No part of this publication may be reproduced or transmitted in any form by any means, without permission of the author. THE DETOXIFICATION APPROACH FOR PATIENTS WITH GHB DEPENDENCE Rama Mohamed Kamal Promotoren: Prof. dr. C.A.J. de Jong Prof. dr. A.J.M. Loonen (RUG) Copromotoren: Dr. A.F.A. Schellekens Dr. B.A.G. Dijkstra Manuscriptcommissie: Prof. dr. R.P.C. Kessels Prof. dr. J.K. Buitelaar Prof. dr. B. Wilffert (RUG) THE DETOXIFICATION APPROACH FOR PATIENTS WITH GHB DEPENDENCE PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus, volgens besluit van het college van decanen in het openbaar te verdedigen op woensdag 3 februari 2016 om 12.30 uur precies door Rama Mohamed Kamal geboren op 8 juni, 1971 te Omdurman (Sudan) Supervisors: Prof. dr. C.A.J. de Jong Prof. dr. A.J.M. Loonen (RUG) Co-supervisors: Dr. A.F.A. Schellekens Dr. B.A.G. Dijkstra Doctoral Thesis Committee: Prof. dr. R.P.C. Kessels Prof. dr. J.K. Buitelaar Prof. dr. B. Wilffert (RUG) THE DETOXIFICATION APPROACH FOR PATIENTS WITH GHB DEPENDENCE DOCTORAL THESIS to obtain the degree of doctor from Radboud University Nijmegen on the authority of the Rector Magnificus, according to the decision of the Council of Deans to be defended in public on Wednesday, February 3, 2016 at 12.30 hours by Rama Mohamed Kamal Born on June 8, 1971 in Omdurman (Sudan) TABLE OF CONTENTS Chapter 1 General introduction p.12 Chapter 2 The Neurobiological Mechanisms of Gamma- Hydroxybutyrate p.32 (GHB) Dependence and Withdrawal and Their Clinical Relevance Chapter 3 Psychiatric Comorbidity Prevalence and Effect on the Pattern of p.64 Gamma-Hydroxybutyrate (GHB) Misuse and Quality of Life of the GHB Dependent Patients Chapter 4 The Effect of Concomitant Substance Abuse on the Gamma- p.80 Hydroxybutyric Acid (GHB) Withdrawal Syndrome Chapter 5 GHB Detoxification by Titration and Tapering A. Detoxification in GHB dependent patients with GHB titration p.98 and tapering: Results of the first pilot B. Detoxification in GHB dependent patients with GHB titration p.110 and tapering: a Nation Wide project Chapter 6 Pharmaceutical gamma-hydroxybutyrate (GHB) in patients with p.132 severe benzodiazepine resistant GHB-withdrawal in the hospital Chapter 7 Decision rules for Outpatient GHB (Gamma-hydroxybutyric acid) p.144 Detoxification Chapter 8 Relapse prevention A. Role of Baclofen in relapse prevention: a case series p.160 B. Baclofen as relapse prevention in the treatment of p.176 Gamma- Hydroxybutyrate (GHB) dependence: an open label study C. Baclofen and GHB (Gamma hydroxybutrate) A Dangerous p.192 Combination 8 Table of Contents Chapter 9 Summary and general discussion p.200 Samenvatting en algemene discussie p.214 Curriculum Vitae p.229 List of Publications p.230 Acknowledgements p.232 9 Chapter 1 General Introduction 1 CHAPTER 1 GENERAL INTRODUCTION This dissertation is the result of frequent clinical encounters with the growing health issue of Gamma hydroxybutyric acid (GHB) dependence in the Netherlands. Over the last decade the popularity and prevalence of illicit recreational GHB use has increased in the Netherlands, leading, according to the Consumer & Safety Committee, to a six-fold increase in the number of incidents and emergency room admissions and aggressive interaction with the forces of law. In 2009, 1200 patients were treated for GHB overdose1. A sharp increase has been reported in the number of patients requesting treatment from addiction care facilities and psychiatric hospitals. Physicians have been confronted with cases of severe GHB withdrawal. The literature provides little information on the process of detoxification from GHB. The published case reports did not provide consensus on a structured, safe and effective GHB detoxification method to be followed, in which life-threatening complications can be avoided or minimized, within medium- care facilities. The best tradition of evidence-based medicine , if there is no evidence available, is that professionals should then be curious and undertake the task of starting their own research, looking for answers which help to improve the daily practice and quality of life of their patients. Therefore, this journey was started in 2009, based on available neuro-pharmacological insights, with the first description of a possible approach to treat these patients2, and expanded, with the aim of developing an efficient and safe detoxification treatment for these patients, which was and still is a challenge. This introductory chapter summarizes (pharmacological) characteristics of GHB, emphasizing the complexity of its effects. First, I will illustrate the function and importance of GHB as an endogenous substance. Then the prevalence of illicit (street) GHB use and the related health risks will be presented, followed by a discussion of GHB dependence and the magnitude of this problem in the Netherlands. Finally, the description of the GHB withdrawal syndrome and the known medical treatment approaches will be presented. This chapter ends with an overview of the aims and an outline of this thesis. GHB as an endogenous compound The complex effects of GHB as a psychoactive substance are partially caused by its endogenous existence. GHB occurs naturally in the human brain and body. It has a structure comparable to that of its precursor gamma aminobutyric acid (GABA). It has been shown that the fetal brain, in humans as well as in other species, contains high concentrations of GHB which drop rapidly after birth3. GHB is broadly distributed in the brain and reaches concentrations of 1-4 μM4. The highest levels of GHB exist within the substantia nigra, thalamus, and 12 General introduction hypothalamus, whereas the cerebellum and certain areas of the cerebral cortex contain the lowest concentrations5, 6. 1 GHB is also found in many peripheral organs such as the kidney, heart, and skeletal muscles, in concentrations considerably higher than those in the whole brain7, 8. Yet, its function in the peripheral tissues is unknown. In the central nervous system, GHB is synthesized through transamination and reduction of GABA9, 10. GABA is converted by GABA aminotransferase into succinic semialdehyde. This is subsequently reduced within cytosol or mitrochondria by succinic semialdehyde reductase, a NADP+-dependent oxido-reductase, or by aldo-keto reductase 7A2 (AKR7A2), producing GHB in cellular perinuclear regions. AKR7A2 appears to be the main physiologically relevant enzyme that synthesises GHB11. The catabolism of GHB involves its oxidation to succinic semialdehyde, followed by its entry into the Krebs cycle as succinate. It appears that the site of GHB degradation varies during development. Two enzymes which appear to be important in this process have been identified in animal experiments: GHB dehydrogenase, responsible for the majority of GHB breakdown in the foetus and young animals, and GHB-ketoacid transhydrogenase, which is responsible for most of GHB metabolism in adult animals5, 12. The existence of endogenous GHB and its connection with GABA and succinic acid as precursors is demonstrated by the clinical observation that a deficiency of succinyl semialdehyde dehydrogenase, the enzyme which normally removes succinyl semialdehyde, which is a precursor of GHB, leads to an abnormal accumulation of GHB13. This is a condition which is associated with severe but often unrecognized psychiatric disorders14, and symptoms which resemble those reported in cases of illicit GHB intoxication. Administration of external GHB can affect the 13 CHAPTER 1 negative feedback control between the precursors, more specifically GABA and GHB, resulting in a dis-balance leading to, for example, a decrease in GABA synthesis. However, it has been suggested that GABA is not the only source of endogenous GHB. Therefore, the probability of the presence of other precursors has to be considered. It has been suggested/shown that endogenous 1,4-butanediol (a component of lipid-diols) may serve as such an alternative precursor for GHB15. Despite the fact that the complete and exact function of endogenous GHB is still unclear, endogenous GHB influences several physiological functions due to its putative function as a neuromodulator and neurotransmitter. This has led to several medical indications for the administration of exogenous GHB, as outlined below. Nevertheless, the effect of and interaction between the endogenous GHB and exogenous GHB is not fully described and was a relevant reason for starting an expanded review to be able to understand this relationship which will be outlined further in this thesis. Medical use of GHB GHB was synthesized for the first time in 1964 by Laborit and colleagues as an analogue of gamma-aminobutyric acid (GABA)16. It differs from this primary inhibitory neurotransmitter by the substitution of a hydroxyl group with an amino group, creating C4H8O312. GHB is a 4-carbon fatty acid chain with a carboxyl group at one end, and hydroxy- functionality at the gamma position. The first described in vivo effects of GHB were hypothermia, hypnosis, anaesthesia, and anticonvulsant effects, without apparent respiratory depression or toxicity. In 1977, GHB started its actual therapeutic career as a hypnotic in sleep disorders17 e.g. ‘essential hypersomnia’18. Studies were conducted to test its effect in the treatment of schizophrenia, but these were unsuccessful19, 20. GHB usage was revived in the last two decades as a medication for the treatment of several disorders, under the name Sodium oxybate21. Sodium oxybate is approved for the treatment of narcolepsy with cataplexy in adult patients in Europe, USA, and Canada (Xyrem®). In the case of this condition, GHB is given orally at bedtime to improve nocturnal sleep quality, thus reducing cataplexy episodes during the day22.